Of all the disease preventative measures devised to date, excluding the sanitation of water, vaccine development has made the greatest contribution to human health. Most of the currently available live attenuated vaccines (LAVs) were developed by serial passage of viruses in tissue culture or chicken embryos, and their attenuated phenotype relies on a very limited number of point mutations, which mainly accumulate in the structural genes. Thus, LAVs induce strong, protective, long-lived immune responses, characterized by a balanced combination of circulating neutralizing antibodies and cellular immunity. However, they demonstrate residual reactogenicity and their reversion to a more pathogenic phenotype during vaccination remains a strong possibility. Inactivated (INVs) and subunit viral vaccines, on the other hand, demonstrate high safety, but induce cellular immunity very inefficiently. They typically require multiple doses to achieve protective immunity, as well as frequent boosters, making the vaccination process lengthy and expensive. In some cases, preparation of samples prior to chemical inactivation also requires high biocontainment conditions.
Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV), chikungunya virus and various other alphaviruses represent a serious public health threat. They continuously circulate in different parts of the world, including South America, Central America and North America. VEEV has a strong potential for use by terrorists and as biological warfare agent. It has been weaponized and can be applied either alone or in combination with other pathogens. VEEV is classified as a category B, select agent. A need still exists for effective antivirals or vaccines against VEEV and other alphavirus infections.
The present invention overcomes previous shortcomings in the art by providing pseudoinfectious alphaviruses (PIV), combining the efficiency of live attenuated vaccines (LAVs), which results from the ability of the PIV genome to replicate and produce subviral particles (SVPs), with the safety of inactivated (INV) viral vaccines, due to the inability of PIV to develop a spreading infection.